This invention relates to methods for reducing substance abuse or even achieving abstinence therefrom and/or blocking substance-mediated euphoria and/or reducing or eliminating substance craving.
A major problem throughout the world is substance abuse, e.g., drug abuse, including cocaine abuse, heroin abuse, alcohol abuse, amphetamine abuse, nicotine abuse, etc. Many resources have been directed toward reducing or eliminating these problems and their enormous social costs. However, these remain largely ineffective.
For example, the current major pharmacological treatment for cocaine abuse and craving, desipramine, though somewhat effective, is limited by a delayed onset of two to three weeks. (Gawin, F. H, Kleber, H. D., "Cocaine abuse treatment: Open pilot trial with desipramine and lithium carbonate," Arch. Gen. Psychiat., 42:903-910, 1984.) During this period, patients experience anticholinergic side effects such as dry mouth and blurry vision without therapeutic benefit; therefore, there is an initial high risk of patients dropping out of desipramine treatment. Moreover, several groups have reported that the direct dopamine agonist, amantadine, and the direct dopamine agonist, bromocriptine, are of use in the treatment of cocaine abuse. (Tennant, F. S., et al., "Double blind comparison of amantadine and bromocriptine for ambulatory withdrawal from cocaine dependence," Arch. Int. Med. 147:109-112, 1987.)
Similarly, various methods have been devised to reduce abuse of other substances such as those mentioned above, most notably smoking (nicotine). However, in all cases, the results are unsatisfactory and improvement is needed.
Mazindol is in widespread clinical use as an anorectic. Its minimal side effects include restlessness and insomnia. Because of its cocaine-like dopamine uptake inhibition, it is of use in both Parkinson's disease and narcolepsy. Although Parkinson's patients are notoriously sensitive to side effects, mazindol is a remarkably well tolerated drug. Out of twelve patients in a recent pilot study of mazindol for Parkinsonism, only two reported even mild side effects. (Delwaid, P. J., et al., "Mazindol in the treatment of Parkinson's disease," Arch. Neurol. 40:788-790, 1983.) In a recent report, unexpectedly, when given blindly to normal healthy adults, the oral clinical dose of mazindol was mildly dysphoric and free of abuse potential. (Chait, et al., "Reinforcing and Subjective Effects of Several Anorectics in Normal Human Volunteers," J. Pharmaceutical Exp. Ther., 1987; 242, 777-83.) However, prior to this invention, mazindol has never been used clinically in managing substance abuse.
With respect to abused amphetamines, it is known preclinically that mazindol chemically blocks their reward effects. However, as usual, such preclinical studies are not reliably predictive of clinical results.